Neurotensin-mediated modulation of CYP19A1 and estrogen homeostasis during inflammation: an integrated network pharmacology, molecular docking and in vivo investigation.

The intricate crosstalk between the immune and endocrine systems maintains physiological homeostasis of an organism by synchronizing immune, reproductive and neuroendocrine functions. The present study employed an integrative framework combining network pharmacology, molecular docking, and in-vivo approaches to investigate the role of neurotensin (NTS) in regulating inflammatory-steroidogenic interactions. Thirty six healthy female mice were randomly assigned to six groups (n = 6/group): control, LPS (1 mg/kg bw), LPS + PD149163 low (NTSR1 agonist; 50 μg/kg bw), LPS + PD149163high (100 μg/kg bw, Only PD149163low, Only PD149163high.. After 32 days, plasma and ovarian samples were collected for biochemical analyses. An in-silico approach was employed to assess the potential interaction of SR48692/NTSR1 antagonist with the key proteins of steroidogenic pathway (CYP19A1,17 ꞵ-HSD, Progesterone receptor). Our findings indicate that LPS markedly suppresses CYP19A1 and estrogen production. Furthermore, NTSR1 activation using PD149163 robustly reverses LPS-driven-CYP19A1 suppression in the brain, ovary, as well as in the plasma plausibly via its potent anti-inflammatory mechanisms. The network pharmacology analysis offers innovative framework that allows for a holistic and systematic analysis of interaction between NTS-associated genes and ovarian inflammation-related targets. Molecular docking analyses support the functional relevance of NTSR1 signaling in steroidogenic regulation. Our results delineate the NTSR1-dependent mechanism that safeguards steroidogenic pathways against inflammatory insults. Altogether, network pharmacology, molecular docking analyses, and experimental validation deepen our insights into neuro-endocrine-immune crosstalk and exhibited NTS as a compelling therapeutic target in alleviating inflammation-driven endocrine disruption. PD149163 presumably protect against the endocrinological disorders arising from inflammation-driven disruption of the HPG axis.